Copyright © 2014 By IYPF All rights reserved Open Access Contents Int. J. Drug Dev. & Res. | July - September 2014 | Vol. 6 | Issue 3 | ISSN 0975-9344 |
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Prediction of novel drug target Involved in psychosis in Alzheimer Disease: A Computational Network study Mrinal Mirsra1
Abstract:
Alzheimer (AD) disease is the most frequent form of dementia. Several structural and functional genomic factors are strongly associated with AD candidate genes, including age of onset, cognitive decline and amyloid depositions. Serotonin (5Febin Prabhu Dass. J1* TH) receptors play an important role in psychosis in AD with cognitive impairment. This study is based on insilco identification and prioritization of the differentially 1 Bioinformatics Division, School of expressed genes of the genetic network involved in AD. Fourteen 5-HT candidate Biosciences and Technology, VIT genes interaction network associated with AD was generated using agilent University, Vellore. Tamil Nadu literature search cytoscape plugin. The organic layout shows cross-interaction State, India. 632014. between the genes set. On merging the genetic network with gene expression 2 Enterprise and Cloud Computing, profile data, notable changes in interaction patterns were observed. These School of Information Technology changes revealed 5-HTR2A, 5-HTR2C and 5-HTR4 as important genes in AD. Further & Engineering, VIT University, refinement with Enrichment Map indicated 5-HTR2C as novel candidate gene that Vellore. Tamil Nadu State, India. showed high functional significance in correlation to Alzheimer's disease. Our result 632014. will be a crucial factor for better understanding of the genetic pathways involved in causing psychosis in AD and will form a future landmark in developing target Corresponding Authors: based drug therapies against this disease. Febin Prabhu Dass. J Associate Professor, Bioinformatics Division, eywords: Within family interaction;co-expression;major target, computational School of Biosciences and network analysis of alzheimers Technology, VIT University, Vellore, Tamil Nadu, India. 632014. Email:
[email protected]
Kiruba Thangam.
R2
Introduction:
receptor (5HT) are associated with hallucinatory
Alzheimer disease (AD) is a neurodegenerative
demented cohorts. 7 major receptors classes (5-
disorder propagating dementia .This is clinically
HT1-7)
characterized
cognitive
comprising a total of 14 distinct mammalian 5-HT
severe
receptor subtypes. Recent genetic studies in AD
neuropsychiatric disturbances. Deregulation of
showed co-existence of several polymorphisms of
serotonergic neurotransmitter system is credited to
the
cause AD on wide scale. The impaired neuronal
neuropsychotic symptoms. Gene polymorphism in
signalling cascades serotonergic deregulation
5-HT receptor resulting in the change of the gene
affecting the proteolysis of the amyloid precursor
expression
protein (APP) and stimulate amyloid formation in
associated with visual and auditory hallucinations
the brain.
or psychosis in patients with AD. A 44–base pair
Although the origin of psychotic symptoms in
(bp) insertion (the long or l form) of the 5-HTT
Alzheimer’s
multi-factorial,
promoter region (5-HTTPR) was reported to be
alterations in serotonergic neurotransmission are
associated with psychosis and aggression in AD. A
often implicated. Polymorphisms of the serotonin
variable
impairment
symptoms and delusions in demented and non-
by
progressive
associated
disease
(AD)
with
is
mediates
serotonin
5-HT
metabolic
neurotransmitter
level
number
has
been
tandem
pathway
genes
reported
repeat
and
to
be
(VNTR)
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Full Length Original Research Paper
Page 147
K
polymorphism in intron 2 of the 5-HTT gene was
Materials and Methods:
unipolar or bipolar depression in AD. The change
Dataset Collection
in the specific genetic expression pattern also
Serotoninergic receptors previously reported to
results in cascading the change in expression
play important role in Brain ageing and based on
pattern to the other associated genes of the
extensive literature searching, we selected 14
genetic network pathway directly or indirectly. This
candidate
change can vary the resulting gene products of
serotoninergic receptors. Collections of expression
diverse genes in the network greatly affecting the
profiles for the 98 important genes involved in the
other different pathways.
genetic network were done from NCBI Geo profile
In our study, Multiple 5-hydroxytryptamine (5-HT)
database.
genes along with other genes of the genetic
Development of genetic network using Cytoscape
network were observed but only few of these 5-HT
Cytoscape
genes when differentially expressed are reported
apprehending networks using Zoomable User
to cause Alzheimer disease (Fig 1). We used
Interface. The directing through this interface is
Cytoscape
for generating and visualising
based on two processes namely zooming and
genetic interaction network. Different Cytoscape
panning. Zooming changes the dimensions of the
plugins were used to assist the generation and
view based on the user need. Panning enables
analysis of the network with extreme accuracy.
the users to direct the focus of a screen to
Obtained
Genetic
different location of a view. Agilent Literature
candidate
genes
[4]
network were
then
comprising
the
prioritize
and
search
[5]
genes
is
which
used
for
code
these
directing
and
was used to scan the genetic network
analyzed by merging with the genetic expression
through published literatures.
of the differentially expressed genes in AD which
within cytoscape and is a meta search tool that
on
map
have a ability of integrating the information and
generated on the basis of differentially expressed
knowledge extraction to generate the genetic
genes regrouping and categorising the genes
network from literatures using Pubmed, OMIM and
corresponding to their expression giving the most
USPTO
refined results.
candidate genes. For generating the genetic
further
analysis
with
enrichment
network
search
it
engines
uses
User
It work parallely
when
fed
with
context-based
the
symbol
normalization. Genetic expression profile data of all the genes of the genetic network from NCBI geoprofile database were extracted and saved as a file in pvals format. The file was merged with normal genetic network. Enrichment map[7] (Fig 2) for
the
differentially
expressed
genes
were
generated for further analysis and refinement of the result which clusters the genes according to correlation with each other giving three clusters of Fig 1: Network before merging genetic map
gene differentiated on the basis of the preference
Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July - September 2014, 6 (3): 147-152 © 2014 Febin Prabhu Dass. J et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
Page 148
Sudha. S et al; The influence of calreticulin on oxidative stress in MCF-7 cells
also reported to associated with susceptibility to
of expression profile data of the differentially expressed genes.
Result and Discussion: Cytoscape is used for generating and
Page 149
visualising the genetic network involved in causing Fig 2: Enrichment Map for the expressed genes
Alzheimer’s disease. We tested the functional
Visualisation of the genetic network
significance
Vizmapper
[6]
was used for assisting the
of
hydroxytryptamine
differentially (5HT)
expressed
genes
in
5-
causing
Visualisation of the genetic network merged with
Alzheimer’s disease. We selected 14 candidate
genetic expression profile data by setting the
genes (5-HT1A, 5-HTR1B, 5-HTR1D, 5-HTR1E, 5HTR1F,
parameters for size and color of the nodes and
5-HTR2A, 5-HTR2B, 5HTR2C, 5-HT4A, 5-HTR4B, 5-
edges according to expression profile data of the
HT5A, 5-HTR5B, 5-HT6 and 5-HT7) for building the
genes (Fig 3). On visualising and analysing the
genetic network involved in causing Alzheimer’s
genetic network merged with expression profile
disease. Fig 1. shows the normal genetic network
data elucidates most potent genes that could be
before merging with genetic expression profile
very crucial in causing Alzheimer disease.
data whose edges and nodes colours and sizes parameters are set according to outdegree of each gene in the network. This network shows HTR1A, HTR2A, HTR6, BIN1, CR1 and APOE having maximum outdegrees distribution [Fig 4] and average clustering coefficient (Fig 5).
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Full Length Original Research Paper
Fig 3: Network after merging genetic map
CLU[8,
9],
IN1[9], PDYN[10], ABCA8[11], HSP90AA1[12],
GRIA2[13],
APP[14],
CAMKV[15],LRP2[16],
PRDM2[17],MAP1B[18] ,BMP7[19] and MTM1[20] are previously reported to play significant role in causing Alzheimer disease. The result obtained in this study reports HTR2C as a significant candidate
observation
will
development Fig 4: Outdegree distribution in the network
of
provide new
a
landmark
drug
targets
for
against
Alzheimer's.
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Date of Acceptance: 29-09-2013 Conflict of Interest: NIL Source of Support: NONE
Page 152
Sudha. S et al; The influence of calreticulin on oxidative stress in MCF-7 cells
Date of Submission: 16-09-2013
Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July - September 2014, 6 (3): 147-152 © 2014 Febin Prabhu Dass. J et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.